1. Field of the Invention
Alpha-lipoic acid is used in pharmaceutical formulations both in infusion solutions as well as in solid galenic formulations for oral use. Synthetically produced, racemic DL-alpha-lipoic acid, also designated as RS-thioctic acid, is used for this.
2. Background Information
An enantiomer of alpha-lipoic acid, R-thioctic acid, occurs as natural substance in practically all animal and vegetable cells. R-thioctic acid is of essential significance as coenzyme in the oxidative decarboxylation of alpha-keto acids (e.g. pyruvic acid). Thioctic acid is pharmacologically active and exhibits antiphlogistic and antinoceceptive (analgetic) as well as cytoprotective properties. An important medical indication is the treatment of diabetic polyneuropathy. Furthermore, thioctic acid is used in cosmetics as well as in the supplementation of nutrition, e.g. on account of its antioxidative action. The use of R-thioctic acid appears to be especially advantageous thereby since it is present in a form identical to nature (see also EP 0,572,922 A1) and is inserted only in the natural form as cofactor into the pyruvate-dehydrogenase complex (Oehring et al., Biol. Chem. Hoppe-Seyler 373, 333-335, 1992). According to recent results (Baur et al., Klin. Wochenschr. 1991, 69(15), 722-4) thioctic acid can possibly become significant in the combating of disease caused by HIV-1- and HTLV IIIB viruses.
In the case of the pure, optical isomers of thioctic acid (R and S form, that is, R-thioctic acid and S-thioctic acid), in contrast to the racemate the R enantiomer is primarily antiphlogistically and the S enantiomer primarily antinociceptively active (see also EP 0,427,247 A2). Therefore, in order to achieve a selective action the production and use of the pure enantiomers are of great importance.
A number of methods are known for the purposeful production of the pure enantiomers of R- or S-thioctic acid which methods generally contain an enantioselective synthesis stage for the production of a suitable chiral precursor or intermediate stage. All previously known methods require a high synthetic expense and exertions to deplete the undesired enantiomer and have up to the present not made an industrialscale use possible.
The melting range of the pure enantiomers of thioctic acid (47 to 49.degree. C.) is lower compared to the racemic compound (58-61.degree. C.). In the production of solid galenic formulations, which generally takes place under pressing or compacting, the use of pressure on the material is indispensable so that on the one hand a heating and on the other hand a melting of the thioctic acid takes place. Concentrated solutions of thioctic acid or its melts polymerize immediately and can no longer be converted into a crystalline form by cooling.
This effect is very pronounced in the case of pure enantiomers of thioctic acid due to the low melting point. The use of basic salts has been suggested for the desirable therapeutic use of the pure enantiomers (see also EP 702,953 A2).